REVIEW
Keratolytics and Emollients and Their Rolein the Therapy of Psoriasis: a Systematic Review
Arnd Jacobi • Anke Mayer • Matthias Augustin
To view enhanced content go to www.dermtherapy-open.comReceived: August 29, 2014 / Published online: January 21, 2015� The Author(s) 2015. This article is published with open access at Springerlink.com
ABSTRACT
Introduction: Psoriasis is a common chronic
disease with significant impairment in quality
of life. As there is no cure, it often requires
lifelong disease control to minimize the
development of skin lesions and to relieve
symptoms. The aim of this publication is to
systematically review the role of currently used
emollients and keratolytics in the treatment of
psoriasis.
Methods: A systematic literature search was
conducted in Medline via PubMed regarding
reviews, meta-analyses, and trials published
from January 1983 to December 2013 dealing
with topical administration of emollients and
keratolytics in patients with psoriasis. A
subsequent search in EMBASE regarding
clinical trials published from 1983 to 2013 was
performed to complement the findings.
Results: A total of 60 publications met the
inclusion criteria for full-text evaluation. While
current reviews, meta-analyses, and guidelines
state that adjuvant therapy with emollients and
keratolytics should be an obligatory part in the
therapy of psoriasis to facilitate descaling
and/or penetration enhancement,
comprehensive trials on these agents are
missing, with the exception of combination
products containing salicylic acid and
corticosteroids. In the mentioned trials,
addition of salicylic acid was beneficial in
inducing a more rapid onset of action as well
as a reduction of severity parameters and the
area affected. However, its use has substantial
limitations in young children, in patients with
renal/hepatic impairment, with widespread
psoriasis, those undergoing phototherapy, or
those concomitantly treated with
calcipotriene/systemic salicylates.
Conclusion: In view of these shortcomings,
there is a need for well-designed studies on
suitable keratolytic alternatives to salicylic acid
offering an indisputable positive benefit–risk
ratio.
Electronic supplementary material The onlineversion of this article (doi:10.1007/s13555-015-0068-3)contains supplementary material, which is available toauthorized users.
A. Jacobi (&) � A. Mayer � M. AugustinInstitute for Health Services Research inDermatology and Nursing (IVDP), German Centerfor Dermatological Research (CeDeF), UniversityMedical Center Hamburg-Eppendorf, Hamburg,Germanye-mail: [email protected]
Dermatol Ther (Heidelb) (2015) 5:1–18
DOI 10.1007/s13555-015-0068-3
Keywords: Alpha-hydroxy acids; Emollients;
Keratolytic agents; Keratolysis; Poly-hydroxy
acids; Psoriasis; Salicylic acid; Skin-peeling
agents; Skin peeling; Urea
INTRODUCTION
Psoriasis is a chronic, immune-mediated,
inflammatory, systemic disease with
predominant skin and joint manifestations. As
such, it has significant implications on physical,
psychological, and social functioning [1–8].
Psoriasis represents one of the most common
chronic inflammatory diseases worldwide,
affecting approximately 2–3% of the
population [4, 5, 7, 9–11]. About 80–90% of
patients with psoriasis have the plaque form of
the disease [3, 10]. Although the majority of
psoriatic cases are mild to moderate in severity,
approximately 20% of patients suffer from
moderate to severe disease as determined by
the percentage of body surface area involved or
the overall degree of erythema, induration, and
desquamation [3]. The impairment in quality of
life due to psoriasis has been found to be
equivalent to that from major systemic diseases
such as arthritis, type 2 diabetes, chronic lung
disease, and myocardial infarction [1, 10, 12].
Currently, topical treatments with
corticosteroids and vitamin D analogs
represent first-line therapies for psoriasis [13].
Topical treatments may also employ calcineurin
inhibitors, dithranol, tazarotene, or tar [14]. In
patients with more severe or treatment-resistant
disease, second- or third-line therapies include
phototherapy, systemic agents such as
methotrexate, and, more recently, biologicals
such as tumor necrosis factor inhibitors. These
therapeutic modalities have been proven to be
highly effective; however, the potential for
long-term toxicity needs to be considered [13].
Phototherapy includes narrow-band ultraviolet
(UV) B, broadband UVB, as well as psoralen and
UVA photochemotherapy [15, 16].
Patient surveys have revealed that, at
present, patients do not receive optimal
treatments and experience insufficient
satisfaction with the efficacy of available
topical treatments as reflected by a high rate
of non-compliance [17–19]. Since in a cyclical
pattern, treatment outcome influences
treatment satisfaction, which in turn affects
medication adherence; the effectiveness of
topical treatments may be improved by
increasing patients’ adherence [18]. Therefore,
and since psoriasis often requires lifelong
therapy, safe, convenient, and effective topical
regimens with good cosmetic acceptance can be
of great benefit in this large patient population
[20].
Current guidelines recommend keratolytics
such as topical preparations containing urea
and salicylic acid as adjuvant therapy for
psoriasis and state that these represent an
internationally recognized standard in the
treatment of all severity states of psoriasis [10].
The claimed benefits of these agents are
specified in Table 1 [3, 4, 6, 21–23].
However, profound and recent evidence on
their efficacy from clinical trials is lacking.
Therefore, the aim of this publication is to
systematically review the role of currently used
emollients and keratolytics in the treatment of
psoriasis to answer the following questions:
• What do authors of recently published
reviews/meta-analyses conclude on the role
of emollients and keratolytics in the
treatment of psoriasis?
• What is the current evidence from clinical
trials on these agents with respect to efficacy
and safety that has been published during
the last 30 years?
2 Dermatol Ther (Heidelb) (2015) 5:1–18
METHODS
Systematic literature searches were performed in
Medline and EMBASE. Literature searches for
relevant articles published within the last
20 years were conducted on December 30,
2013 in Medline via PubMed using the
following search term: ‘‘(1993/01/01:2013/11/
30[dp] OR 1993/01/01:2013/11/30[edat]) AND
psoriasis AND (keratolysis OR keratolytic OR
salicylic acid OR urea)’’. The results were further
confined using specific qualifier words
regarding efficacy, safety, or type of
publication, for example, ‘‘therapeutic use’’,
‘‘efficacy’’, ‘‘effectiveness’’, ‘‘safety’’,
‘‘tolerability’’, ‘‘toxicity’’, ‘‘review’’, ‘‘meta-
analysis’’, ‘‘practice guideline’’, ‘‘clinical trial’’,
or ‘‘randomized controlled trial’’. The search
yielded a total of 798 articles for consideration.
All hits were reviewed based on abstracts and/or
Medical Subject Headings (MeSH) terms.
Articles that did not specifically deal with the
safety and efficacy of emollients or keratolytics
in the treatment of psoriasis but dealt with
other psoriasis treatments such as hydroxyurea
or topical retinoids, with other indications or
other topics or subjects (e.g., methods papers,
non-clinical, mechanistic studies) were
excluded. This applied to the majority of
retrieved publications (approximately 90%).
Because salicylic acid is frequently added to
dithranol for the prevention of dithranol
oxidation, all publications on the combination
of salicylic acid and dithranol were excluded
[24]. The same applies to efficacy trials
conducted in healthy volunteers or in patients
with disorders other than psoriasis. Whereas
clinical studies investigating keratolytics vs.
baseline, placebo, no treatment, or other
keratolytics and combination therapy vs. the
respective monotherapy without penetration
enhancement were considered eligible for
inclusion, articles that dealt with the safety or
efficacy of conventional keratolytics in
combination therapies for psoriasis but did not
investigate the monosubstances and did thus
not allow drawing conclusions about their
specific effect were not considered
(approximately 2% of hits). Articles that were
not written in English or German were excluded
(approximately 2% of hits). Guidelines or
reviews which had already been revised were
not considered. Since the number of articles
providing evidence on the role of conventional
keratolytics in the therapy of psoriasis
published in the last 20 years was limited, the
search period was extended to the last 30 years.
The searches for relevant literature published
between 1983 and 1993 were conducted in
Medline via PubMed using the following search
terms: ‘‘psoriasis AND (keratolytic[Majr] OR
salicylic acid[Majr] OR urea[Majr])’’, ‘‘psoriasis
AND (keratolysis OR keratolytic) AND (rct OR
randomized controlled trial)’’ and ‘‘psoriasis AND
(salicylates[Majr])’’. Using the above-mentioned
selection criteria, a total of 53 guidelines, meta-
analyses, reviews, and clinical trials published in
German or English language from January 1983
to December 2013 and dealing with topical
administration of keratolytics in patients with
psoriasis were regarded as potentially relevant
Table 1 Main objectives of using keratolytics in psoriasis
Main objectivesa
• Softening/hydration of the stratum corneum
• Desquamation of hyperkeratotic skin
• Relieve of pruritus/discomfort
• Barrier repair
• Penetration enhancement of topically applied
anti-psoriatic drugs/ultraviolet radiation
during phototherapy
a Cited according to published reviews [3, 4, 6, 21–23]
Dermatol Ther (Heidelb) (2015) 5:1–18 3
and selected for full-text assessment. After full-
text review, seven articles were excluded as they
did not refer to emollients or keratolytics (n = 2)
or did not compare combination therapy vs. the
respective monotherapy without penetration
enhancement (n = 5).
Since Medline may not have revealed all
relevant publications (i.e., clinical trials),
additional searches for original literature on
psoriasis published in English or German
language between 1983 and 2013 were
performed in EMBASE using the qualifier
‘‘clinical trial’’ and the controlled terms
‘‘keratolytic agent’’, ‘‘salicylic acid’’, and ‘‘urea’’.
These searches yielded a total of 41 articles for
consideration, of which 3 articles had not
previously been identified in Medline. The
selection was further complemented by
publications that were cited in the articles
identified by the systematic literature searches
and by including relevant current guidelines on
psoriasis treatment as well as references therein
(n = 11).
The results section of this paper consists of
four subsections referring to the group of
emollients and major keratolytic agents, each
starting with a paragraph that contains
information on the mechanism of action and
evidence of the efficacy and safety as extracted
from reviews, meta-analyses, and/or guidelines.
This information is followed by the data on
efficacy and safety derived from published
clinical trials. This review is based on
previously conducted studies and does not
involve any new studies of human or animal
subjects performed by any of the authors.
RESULTS
From systematic literature searches conducted
in Medline via PubMed and EMBASE, a total of
49 publications met the inclusion criteria for
this review. Furthermore, the reference lists of
included publications were scrutinized for
additional studies published in January 1983
or later, adding 11 publications to the selection.
Thus, a total of 60 publications were reviewed.
Emollients
Emollients induce an occlusive film that limits
evaporation of water from deeper parts of the
skin and allows the stratum corneum to
rehydrate itself. The application of natural
moisturizing factors induces an increase in the
water-binding capacity of the stratum corneum
[21]. Regular application of emollients improves
comfort and reduces scaling, fissuring [1], and
itching in patients with plaque or scalp psoriasis
[25, 26]. Additionally, emollients may increase
the efficacy of topical corticosteroids by
improving the penetration through the skin
layers [21, 27, 28]. Guidelines of care for the
management of psoriasis and psoriatic arthritis
state that when used as a control in topical
steroid trials, non-medicated topical
moisturizers demonstrated a response rate
ranging from 15 to 47% [21, 27]. This broad
range may reflect the great variability of their
composition; however, in the corresponding
guideline dealing with topical therapies, the
individual composition of the moisturizers has
not been specified [7]. Emollients are usually
well tolerated [23]. However, they can cause
side effects such as irritant dermatitis, allergic
contact dermatitis, fragrance allergy or allergy
to other constituents, stinging, cosmetic acne,
and pigmentary disorders [21]. In addition,
some reports indicate a potential penetration-
enhancing effect of the stratum corneum to
irritants after long-term use [21]. In clinical and
experimental settings it has been shown that
4 Dermatol Ther (Heidelb) (2015) 5:1–18
some emollients, e.g., oil-in-water emollient
enhance the penetration of UVA or UVB when
used before irradiation, thus increasing the
efficacy of phototherapy [29, 30]. However,
in vitro studies and studies in healthy
volunteers also demonstrated a blocking effect
of other emollients, such as white petrolatum
[31] and the emollient cream Eucerin
(Beiersdorf Inc., Wilton, CT, USA), consistent
with their thickness [32].
While 3 small clinical trials including a total
of 111 patients provide limited evidence that,
compared to baseline, emollients used as a
monotherapy may improve skin hydration,
barrier function, as well as proliferation and
differentiation markers in patients with
psoriasis [11, 33, 34], the clinical response
showed only a slight symptomatic
improvement of psoriasis [33]. Due to
inconsistent results from randomized
controlled trials, there is limited evidence of a
steroid-sparing effect of emollients when used
in combination with corticosteroids. In the
evaluated studies, only two adverse events of
pruritus and folliculitis (each n = 1) were
reported (see Table 2) [11, 33–37].
Urea
Urea is known to exert proteolytic, keratolytic,
hydrating, hygroscopic, penetration-
enhancing, epidermis-thinning, and anti-
pruritic effects. The moisturizing action of
urea in dry and scaly skin conditions has been
widely studied and is well accepted [21, 38].
Fluhr et al. [21] suggested that lipid biosynthesis
may be increased by topical application of
highly concentrated urea. In vitro and in vivo
data showed a reduction of DNA synthesis in
the cells of the basal layers (by approximately
45%), a thinning of the epidermis (by
approximately 20%), a reduction of the
epidermal cells, and a prolongation of the
generation time of postmitotic epidermal cells
[21, 39]. Therefore, urea has been shown to
reduce epidermal hyperproliferation and to
induce cell differentiation [27]. As a
mechanism of action it has been hypothesized
that urea may break hydrogen bonds and
interfere with the quaternary structure of
keratin thus dispersing and denaturizing
keratin without disrupting the epidermal water
barrier. Pre-treatment or concomitant
treatment with urea may also enhance the
efficacy of other topical therapies [39]. Due to
its safety, urea-containing preparations
represent the standard in the adjuvant therapy
of juvenile psoriasis [5]. Only non-systemic side
effects have been reported, with mild irritation
being the most common, making urea a safe
and well-tolerated topical drug [39].
While a small, older comparative study
found no statistical differences on severity
parameters such as scaling, erythema, and
infiltration compared to the vehicle [40], in
another trial using the same preparation,
treatment for 1 week led to a statistically
significant improvement of scaling compared
to the vehicle (see Table 3) [38, 40–46]. This is in
line with two further studies in which severity
parameters of psoriasis such as scaling and/or
induration were reduced with urea in
monotherapy [39]. Of these, in a small
randomized, double-blind study, addition of
10% urea to the vehicle was significantly more
effective regarding epidermal proliferation,
stratum corneum hydration, and epidermal
thickness with a 60% reduction of the clinical
psoriasis severity score of scaling and a 32%
reduction of induration (see Table 3) compared
to the vehicle alone [38]. The ointment base
also improved psoriasis, but urea was
significantly more effective showing a 40%
reduction in epidermal proliferation compared
Dermatol Ther (Heidelb) (2015) 5:1–18 5
Tab
le2
Effi
cacy
and
safe
tyof
emol
lient
sin
clin
ical
tria
ls
Ref
eren
ces
Inte
rven
tion
Tre
atm
ent
dura
tion
Pop
ulat
ion
Stud
yde
sign
Res
ults
Adv
erse
even
ts
van D
uijn
hove
n
etal
.[33
]
50%
crem
orla
nett
eI
inva
selin
um
albu
m
2w
eeks
5pa
tien
ts
wit
h
psor
iasi
s
Non
-com
para
tive
stud
yN
orm
aliz
atio
nof
prol
ifera
tion
and
diff
eren
tiat
ion
mar
kers
;sli
ght
impr
ovem
ent
com
pare
dto
base
line
Non
e
repo
rted
Rim
etal
.
[34]
Pseu
doce
ram
ide
(myr
isty
l/
palm
ityl
oxos
tear
amid
e/
arac
ham
idem
onoe
than
olam
ine)
6w
eeks
17pa
tien
ts
wit
h
psor
iasi
s
Con
trol
led
stud
y(v
s.
untr
eate
dle
sion
s)
Impr
oved
visu
alas
sess
men
tof
skin
dryn
ess,
sign
ifica
ntly
incr
ease
d
elec
tric
alca
paci
tanc
e;de
crea
sed
TE
WL
Mild pr
urit
usin
one
pati
ent
Paup
orte
etal
.
[11]
Com
bina
tion
ofpe
anut
and
min
eral
oil
3w
eeks
89pa
tien
ts
wit
h
mod
erat
e
tose
vere
scal
p
psor
iasi
s
Ran
dom
ized
,con
trol
led,
doub
le-b
lind
stud
y(v
s.
0.01
%
fluoc
inol
onea
ceto
nide
)
Impr
ovem
ent
ofal
lsi
gns
ofps
oria
sis
com
pare
dto
base
line
(P\
0.05
)
Tre
atm
ent-
rela
ted
folli
culit
is
inon
e
pati
ent
Tan
ghet
ti
etal
.[35
]
Com
bina
tion
ofta
zaro
tene
wit
h
anem
ollie
nt(n
otfu
rthe
r
spec
ified
)
12w
eeks
1,39
3
pati
ents
wit
h
plaq
ue
psor
iasi
s
Obs
erva
tion
alst
udy
Enh
ance
def
ficac
yof
taza
rote
ne;
incr
ease
dpa
tien
tssa
tisf
acti
on
Non
e
repo
rted
Wat
sky
etal
.
[36]
Com
bina
tion
of0.
05%
beta
met
haso
nedi
prop
iona
te
and
aw
ater
-in-o
ilba
sed
moi
stur
izin
gcr
eam
orlo
tion
(not
furt
her
spec
ified
)
4w
eeks
96pa
tien
ts
wit
h
chro
nic
plaq
ue-t
ype
psor
iasi
s
Con
trol
led,
open
labe
l
stud
y(t
wic
eda
ilyvs
.
once
daily
)
Onc
e-da
ilyap
plic
atio
nw
aseq
uiva
lent
inef
ficac
yto
twic
e-da
ilyap
plic
atio
n
and
sign
ifica
ntly
bett
erth
anon
ce-
daily
appl
icat
ion
ofbe
tam
etha
sone
alon
e(b
oth
P=
0.05
)
Non
e
repo
rted
Sing
het
al.
[37]
Com
bina
tion
of0.
05%
beta
met
haso
nedi
prop
iona
te
twic
eda
ilyin
prop
ylen
egl
ycol
9da
ys36
pati
ents
wit
h
psor
iasi
s
Ran
dom
ized
,con
trol
led,
doub
le-b
lind
stud
y(v
s.
once
-dai
ly
beta
met
haso
ne)
No
diff
eren
ceco
mpa
red
toon
ce-d
aily
beta
met
haso
nere
gard
ing
eryt
hem
a,
scal
ing,
indu
rati
onan
dL
PSI
Non
e
repo
rted
LPS
IL
ocal
Psor
iasi
sSe
veri
tyIn
dex,
tew
ltr
anse
pide
rmal
wat
erlo
ss
6 Dermatol Ther (Heidelb) (2015) 5:1–18
Tab
le3
Effi
cacy
and
safe
tyof
urea
incl
inic
altr
ials
Ref
eren
ces
Inte
rven
tion
Tre
atm
ent
dura
tion
Pop
ulat
ion
Stud
yde
sign
Res
ults
Adv
erse
even
ts
Gip
etal
.[40
]12
%ur
eaan
d12
%
sodi
umch
lori
de
3w
eeks
30pa
tien
tsw
ith
psor
iasi
s
Con
trol
led
doub
le-b
lind
stud
y(v
s.ve
hicl
e)
No
stat
isti
cal
diff
eren
ces
on
seve
rity
para
met
ers
such
as
scal
ing,
eryt
hem
aan
din
filtr
atio
n
com
pare
dto
vehi
cle
Bur
ning
sens
atio
n
intw
o
pati
ents
Fred
riks
son
etal
.
[41]
12%
urea
and
12%
sodi
umch
lori
de
1w
eek
40pa
tien
tsw
ith
psor
iasi
s
Con
trol
led
stud
y(v
s.
vehi
cle)
Stat
isti
cally
sign
ifica
nt
impr
ovem
ent
insc
alin
g
com
pare
dto
vehi
cle
Non
e
repo
rted
Hag
eman
nan
d
Prok
sch
[38]
10%
urea
2w
eeks
10pa
tien
tsw
ith
psor
iasi
s
Ran
dom
ized
,con
trol
led,
doub
le-b
lind
stud
y(v
s.
vehi
cle
and
vs.
untr
eate
dsi
te)
Red
ucti
onof
the
clin
ical
psor
iasi
s
seve
rity
scor
esof
scal
ing
(-60
%)
and
indu
rati
on(-
32%
;
P\
0.02
5)co
mpa
red
toth
e
vehi
cle;
two-
fold
incr
ease
in
stra
tum
corn
eum
hydr
atio
n
(P\
0.01
)co
mpa
red
toth
e
untr
eate
dsi
te
Non
e
repo
rted
Lak
shim
ian
d
Bha
skar
an[4
2]
10%
plai
nur
eage
lor
5%ur
eani
osom
al
gel
12w
eeks
40ad
ult
pati
ents
wit
h
stab
lepl
aque
psor
iasi
s
invo
lvin
g\
25%
ofth
e
body
surf
ace
area
or
palm
opla
ntar
psor
iasi
s
Dou
ble-
blin
dpl
aceb
o
cont
rolle
dst
udy
The
nios
omal
urea
gel
prod
uced
grea
ter
redu
ctio
nin
tota
lsc
ore
and
desq
uam
atio
nsc
ore
com
pare
dto
the
plai
nge
lan
d
plac
ebo
(P\
0.05
).B
oth
gels
wer
eeq
ually
effe
ctiv
ein
redu
cing
the
eryt
hem
aan
din
filtr
atio
n
Non
e
repo
rted
Shem
eret
al.[
44]
Com
bina
tion
of40
%
urea
and
1%
bifo
nazo
le
2w
eeks
52pa
tien
tsw
ith
psor
iasi
sca
piti
s;19
pati
ents
wit
hsc
alp
sebo
rrhe
icde
rmat
itis
Non
-com
para
tive
,ope
n-
labe
lst
udy
Impr
ovem
ent
in10
0%of
pati
ents
wit
hco
mpl
ete
heal
ing
in73
.2%
com
pare
dto
base
line
Non
e
repo
rted
Dermatol Ther (Heidelb) (2015) 5:1–18 7
Ta
ble
3co
ntin
ued
Ref
eren
ces
Inte
rven
tion
Tre
atm
ent
dura
tion
Pop
ulat
ion
Stud
yde
sign
Res
ults
Adv
erse
even
ts
Tau
beet
al.[
46]
Com
bina
tion
of1%
dith
rano
lan
d10
%
urea
(aft
er2
days
of
pre-
trea
tmen
tw
ith
5%sa
licyl
icac
id)
7w
eeks
57pa
tien
tsw
ith
psor
iasi
svu
lgar
is
Con
trol
led
case
stud
y
(vs.
dith
rano
lal
one)
Sign
ifica
ntly
shor
tene
dm
ean
trea
tmen
tdu
rati
onun
til
com
plet
ere
solu
tion
of3.
5w
eeks
com
pare
dto
4.2
wee
ksin
the
dith
rano
lon
lygr
oup
Non
e
repo
rted
Ven
aet
al.[
43]
Com
bina
tion
of2%
urea
[bet
amet
haso
ne
dipr
opio
nate
and
calc
ipot
riol
for
4w
eeks
follo
wed
by
calc
ipot
riol
alon
eor
wit
hur
ea(2
%an
d
4%;
once
daily
each
)]
4?
8w
eeks
313
adul
tpa
tien
tsw
ith
psor
iasi
svu
lgar
is
Mul
tice
nter
open
stud
yA
fter
the
8-w
eek
mai
nten
ance
trea
tmen
tph
ase,
the
clin
ical
scor
e
for
eryt
hem
a,sc
alin
g,in
filtr
atio
n
and
prur
itus
impr
oved
inbo
th
grou
ps,w
ith
ate
nden
cyto
war
dsa
grea
ter
redu
ctio
nof
infil
trat
ion
inth
ose
trea
ted
wit
hur
ea.A
grea
ter
perc
enta
geof
pati
ents
conc
omit
antly
trea
ted
wit
hur
ea
(47%
)th
anth
ose
trea
ted
wit
h
calc
ipot
riol
(33%
)ju
dged
the
effic
acy
asex
celle
nt
Bur
ning
sens
atio
n
intw
o
pati
ents
8 Dermatol Ther (Heidelb) (2015) 5:1–18
to the vehicle [38]. Similar results were
demonstrated in a double-blind, placebo-
controlled study, in which two urea gel
formulations (10% plain urea gel or 5% urea
niosomal gel) produced a reduction in
erythema, infiltration, and desquamation, as
well as in the total psoriasis area and severity
index (PASI) score, with the 5% urea niosomal
gel being more effective regarding
desquamation compared to the plain gel and
placebo. However, the percentage of affected
area was not influenced [42]. From three small
studies, limited evidence is known for an
enhanced efficacy of other topical agents such
as bifonazole, dithranol or betamethasone
dipropionate and calcipotriol leading to a
shortened treatment duration (see Table 3)
[43–45]. In the evaluated clinical studies, a
burning sensation was observed in three
patients (see Table 3) [39, 42].
Alpha-Hydroxy Acids and Poly-Hydroxy
Acids
Alpha-hydroxy acids (AHAs), most notably
glycolic acid and lactic acid, are used in
chemical-peel solutions to exfoliate thickened
skin in hyperkeratotic conditions. However,
their use in the treatment of psoriasis has only
recently been advocated and, thus, they are not
mentioned as keratolytic agents in relevant
psoriasis guidelines [7, 17]. AHAs penetrate the
epidermis, inducing an increase in stratum
corneum turnover and cause desquamation of
the outermost layer without impairing barrier
function [21]. They reduce intercorneocyte
bonds by increasing the distance between
corneocytes due to increased stratum corneum
water content, by reducing the charges on the
surface of cells, by inhibiting enzymes involved
in the cohesion between corneocytes, and by
breaking desmosomes as they diminish the pH
of the medium. This reduction can also degrade
keratinocytes directly, thus promoting cell
proliferation. In the dermis, AHAs can
stimulate the biosynthesis of
glycosaminoglycans, collagen, and other
substances, which cause thickening of the skin
[47]. Poly-hydroxy acids (PHAs) also aid in
dermal expansion and can provide the
components for glycosaminoglycans. PHAs
have anti-oxidant and moisturizing properties
and may provide protection of psoriatic skin
with a disrupted skin barrier. When used in
combination with topical corticosteroids, AHAs
or PHAs exert a synergistic effect and reduce
steroid-induced skin atrophy [3].
For AHAs and PHAs, results from 3 small
clinical studies including 57 patients in total are
available. One of these trials, a small, controlled
study, demonstrated that glycolic acid in
monotherapy may lead to significant
reduction in hyperkeratosis and erythema as
compared to baseline, which was comparable to
that achieved with 0.05% betamethasone
valerate (see Table 4) [3, 47, 48]. In a small,
short-term study, AHA/PHA and salicylic acid
exhibited similar efficacy with regard to the
reduction of scaling when compared to baseline
(see Table 4) [3]. The third small study found a
synergistic effect of 10% glycolic acid in
combination with topical corticosteroids
leading to reduced treatment duration and an
increased healing rate (see Table 4) [48]. In the
evaluated studies, no treatment-related adverse
events were reported (see Table 4).
Salicylic Acid
Salicylic acid is the most commonly used and
most thoroughly studied of the currently
known keratolytic compounds [21]. In
concentrations of 5% and above, it exerts an
increasingly potent, rapid, and deep keratolytic
Dermatol Ther (Heidelb) (2015) 5:1–18 9
Tab
le4
Effi
cacy
and
safe
tyof
AH
Aan
dPH
Ain
clin
ical
tria
ls
Ref
eren
ces
Inte
rven
tion
Tre
atm
ent
dura
tion
Pop
ulat
ion
Stud
yde
sign
Res
ults
Adv
erse
even
ts
Ber
arde
sca
etal
.[47
]
15%
glyc
olic
acid
15da
ys12
pati
ents
wit
h
psor
iasi
s
Con
trol
led
stud
y(v
s.
0.05
%
beta
met
haso
ne
vale
rate
)
Sign
ifica
ntly
decr
ease
dT
EW
Lan
d
Las
erD
oppl
erva
lues
;re
duct
ion
in
hype
rker
atos
isan
der
ythe
ma
com
pare
dto
base
line
bein
g
equi
vale
ntto
that
afte
r0.
05%
beta
met
haso
neva
lera
te
Non
ere
port
ed
Aka
min
e
etal
.[3]
15%
AH
As
(lac
tic
acid
,
man
delic
acid
and
gyco
lic
acid
)an
d5%
PHA
s
(glu
cono
lact
one
and
mal
tobi
onic
acid
)
2w
eeks
25pa
tien
tsw
ith
mod
erat
e,
chro
nic,
plaq
ue
psor
iasi
s
Ran
dom
ized
,
cont
rolle
d,do
uble
-
blin
dst
udy
(vs.
6%
salic
ylic
acid
)
Sign
ifica
ntim
prov
emen
tin
scal
ing,
eryt
hem
a,in
dura
tion
and,
Inve
stig
ator
glob
alas
sess
men
t,
com
pare
dto
base
line
Mild
adve
rse
even
ts
asse
ssed
asno
t
rela
ted
infiv
e
pati
ents
Kos
tare
los
etal
.[48
]
Com
bina
tion
of10
%
glyc
olic
acid
and
0.1%
beta
met
haso
ne
8w
eeks
20pa
tien
tsw
ith
scal
pan
d
sebo
rrho
eic
psor
iasi
s
Con
trol
led,
doub
le-
blin
dst
udy
(vs.
beta
met
haso
ne
alon
e)
Red
uced
dura
tion
oftr
eatm
ent
to
appr
oxim
atel
yha
lfco
mpa
red
to
trea
tmen
tw
ith
beta
met
haso
ne
alon
e,8
out
of13
ofth
etr
eate
dsi
tes
heal
edco
mpl
etel
yco
mpa
red
to3
out
of12
wit
hbe
tam
etha
sone
only
Non
ere
port
ed
AH
Aal
pha-
hydr
oxy
acid
,PH
Apo
ly-h
ydro
xyac
id,T
EW
Ltr
anse
pide
rmal
wat
erlo
ss
10 Dermatol Ther (Heidelb) (2015) 5:1–18
effect on the stratum corneum which leads to
descaling [31]. As a mechanism of action, it is
suggested that salicylic acid reduces
intercellular cohesion between corneocytes by
dissolving the intercellular cement material and
reducing the pH of the stratum corneum,
thereby increasing hydration and softening [3,
7, 31]. Topical salicylates also reduce pruritus
[26] and, at concentrations of C0.3%, they
possess bacteriostatic and bactericidal activity
against yeast and Gram-negative and Gram-
positive bacteria [22]. In their clinical guide,
Naldi and Rzany [9] state that there is consensus
that salicylic acid is an effective initial and
adjunctive treatment in chronic plaque
psoriasis. It is most beneficial in extremely
thick or scaly psoriatic plaques [22]. According
to current guidelines, salicylic acid promotes
skin availability of other topical therapies
including topical corticosteroids due to its
keratolytic and penetration-enhancing effect
[1, 7, 14, 20, 49]. This leads to improved
efficacy of other topical treatments. While
salicylic acid is commonly applied and
effective when used as a pre-treatment before
phototherapy [15, 16], topically administered
salicylic acid, in concentrations C0.1%, is
photoprotective [31]. Thus, application of
salicylic acid before UVB phototherapy is not
recommended [15, 16, 22, 32, 50, 51].
According to the evaluated reviews, topical use
of salicylic acid is limited by the risk of chronic
or acute systemic intoxication [2, 7] with
symptoms such as oral pain, headache, central
nervous system symptoms, dizziness, metabolic
acidosis, tinnitus, nausea, vomiting, and gastric
symptoms, as well as hyperventilation [2, 3, 52].
These symptoms may occur after prolonged
topical treatment of large body surfaces (i.e.,
[20%) [6, 7, 25], especially in children under
12 years of age and in patients with significant
renal or hepatic impairment [2, 3, 7, 22, 25].
Local irritation such as stinging, burning, dry
skin, peeling, scaling, or contact dermatitis was
also reported [1, 9, 53]. Temporary shedding of
telogen hair has been observed when used in
the treatment of scalp psoriasis [26].
Concomitant use of other drugs, which may
contribute to elevated serum salicylate levels,
should be avoided [7]. There is an increased risk
for developing toxicity to other topically
applied agents used concurrently, as salicylic
acid may increase their skin penetration [3]. In
addition, topical use of salicylic acid can reduce
the efficacy of calcipotriol [2].
Monotherapy
Regarding monotherapy, three studies on
salicylic acid including 65 patients were
evaluated [54–56]. Of these, an open-label, pilot
study demonstrated that 6% salicylic acid used as
a monotherapy was highly effective, well
tolerated, and acceptable in 10 patients with
scalp psoriasis [54]. All psoriasis severity
parameters as well as the percentage of affected
area were reduced with a significant decrease
in Psoriasis Scalp Severity Index score from
15.3 to 3.0 after 4 weeks of monotherapy when
compared to baseline (P\0.001). A total of 60%
of patients were either ‘‘completely cleared’’ or
‘‘almost cleared’’ (see Table 5) [54]. In a
randomized, double-blind study in 25 patients
investigating 6% salicylic acid vs. 20% AHA/PHA
cream (see also Table 4), both topical agents
resulted in significant improvement of scaling,
erythema, and induration, as well as investigator
global assessment, at the end of week 1 and 2 and
exhibited similar efficacy in reducing scaling.
However, the extent of affected area was not
investigated in this study (see Table 5) [3].
Similar results were obtained in an earlier,
randomized controlled trial reporting successful
treatment of moderate or severe scalp psoriasis
with 6% salicylic acid in 30 patients, including
Dermatol Ther (Heidelb) (2015) 5:1–18 11
Tab
le5
Effi
cacy
and
safe
tyof
salic
ylic
acid
incl
inic
altr
ials
Ref
eren
ces
Inte
rven
tion
Tre
atm
ent
dura
tion
Pop
ulat
ion
Stud
yde
sign
Res
ults
Adv
erse
even
ts
Kir
cik
[54]
6%sa
licyl
icac
id4
wee
ks10
pati
ents
wit
hsc
alp
psor
iasi
sN
on-
com
para
tive
,op
en-la
bel,
pilo
tst
udy
Sign
ifica
ntde
crea
sein
PSSI
scor
efr
om15
.3to
3.0
com
pare
dto
base
line
(P\
0.00
1);
60%
ofpa
tien
tsw
ere
eith
er‘‘c
ompl
etel
ycl
eare
d’’o
r‘‘a
lmos
tcl
eare
d’’
Non
ere
port
ed
Aka
min
eet
al.[
3]6%
salic
ylic
acid
2w
eeks
25pa
tien
tsw
ith
mod
erat
e,ch
roni
c,pl
aque
psor
iasi
sR
ando
miz
ed,
cont
rolle
d,do
uble
-blin
dst
udy
Sign
ifica
ntim
prov
emen
tin
scal
ing,
eryt
hem
a,in
dura
tion
and
inve
stig
ator
glob
alas
sess
men
tco
mpa
red
toba
selin
e
Mild
adve
rse
even
tsas
sess
edas
not
rela
ted
infiv
epa
tien
ts
Goi
nget
al.
[55]
6%sa
licyl
icac
id3
and
6w
eeks
30pa
tien
tsw
ith
mod
erat
eor
seve
resc
alp
psor
iasi
sR
ando
miz
ed,
cont
rolle
dst
udy
65–9
0%of
pati
ents
impr
oved
rega
rdin
gsc
alin
gan
dpe
rcen
tage
ofaf
fect
edar
eaco
mpa
red
toba
selin
e;sc
alin
gsc
ores
for
out-
pati
ents
impr
oved
from
7.0
to4.
5at
6w
eeks
(P\
0.01
)an
dfo
rin
-pat
ient
sfr
om7.
7to
3.7
at3
wee
ks(P
\0.
001)
Dry
ness
and
stin
ging
insi
xpa
tien
ts;
irri
tati
onin
thre
epa
tien
ts
Elie
etal
.[5
7]C
ombi
nati
onof
2%sa
licyl
icac
idan
d0.
05%
beta
met
haso
nedi
prop
iona
telo
tion
21da
ys40
pati
ents
wit
her
ythe
mat
ous
squa
mou
sde
rmat
oses
ofth
esc
alp
incl
udin
g22
pati
ents
wit
hm
oder
ate
tose
vere
psor
iasi
s
Ran
dom
ized
,co
ntro
lled
stud
y
Red
ucti
onof
mea
nto
tal
dise
ase
sign
scor
esfo
rsc
alin
gaf
ter
14an
d21
days
(P\
0.05
),er
ythe
ma
afte
r14
days
(P\
0.02
)an
daf
ter
21da
ys(P
\0.
01),
prur
itus
afte
r14
and
21da
ys(P
\0.
01);
phys
icia
n’s
glob
alev
alua
tion
show
eda
bett
erev
olut
ion
afte
r14
days
(P\
0.01
)an
daf
ter
21da
ys(P
\0.
02)
com
pare
dto
beta
met
haso
nedi
prop
iona
teal
one
Non
ere
port
ed
Nol
ting
and
Hag
emei
er[5
6]
Com
bina
tion
of2%
salic
ylic
acid
and
0.05
%be
tam
etha
sone
dipr
opio
nate
solu
tion
3w
eeks
100
pati
ents
(n=
36w
ith
psor
iasi
svu
lgar
is)
Ran
dom
ized
,co
ntro
lled
stud
y
Mor
era
pid
onse
tof
acti
onan
da
mor
era
pid
clea
ring
ofsc
alin
g,pr
urit
usan
din
flam
mat
ion;
decr
ease
dpr
urit
us(1
00%
vs.7
6%)
wit
hbe
tam
etha
sone
dipr
opio
nate
alon
e
Non
ere
port
ed
Tip
lica
and
Sala
vast
ru[5
8]
Com
bina
tion
of5%
salic
ylic
acid
and
0.1%
mom
etas
onef
uroa
teoi
ntm
ent
7da
ys35
9pa
tien
tsw
ith
Ran
dom
ized
,co
ntro
lled,
open
-labe
lst
udy
Sign
ifica
ntly
grea
ter
redu
ctio
nin
PASI
scor
e(P
=0.
0017
);be
tter
trea
tmen
tev
alua
tion
bypa
tien
ts(P
=0.
003)
;si
gnifi
cant
low
erD
LQ
Isc
ores
rega
rdin
g‘sy
mpt
oms
and
feel
ings
’(P
=0.
0464
)an
d‘p
erso
nal
rela
tion
ship
s’(P
=0.
0378
)co
mpa
red
tom
omet
ason
efur
oate
alon
e
Skin
irri
tati
onin
one
pati
ent
Kat
zet
al.
[59]
Com
bina
tion
of5%
salic
ylic
acid
and
0.1%
mom
etas
onef
uroa
teoi
ntm
ent
3w
eeks
341
pati
ents
wit
hm
oder
ate-
to-s
ever
eps
oria
sis
Ran
dom
ized
,co
ntro
lled
stud
y
Sign
ifica
ntim
prov
emen
tin
tota
ldi
seas
esi
gnsc
ores
onda
y15
(P=
0.04
)an
don
day
22(P
=0.
01);
impr
ovem
ents
insc
alin
gan
din
dura
tion
(eac
hP
=0.
01)
onda
y22
com
pare
dto
mom
etas
onef
uroa
teal
one
App
licat
ion-
site
reac
tion
ssu
chas
burn
ing,
prur
itus
and
skin
atro
phy
in20
%of
pati
ents
vs.
13%
wit
hm
omet
ason
efur
oate
alon
e
12 Dermatol Ther (Heidelb) (2015) 5:1–18
10 in-patients and 20 out-patients [55]. In-
patients were treated for 3 weeks with daily
applications of 6% salicylic acid removed with a
shampoo 24 h later. Out-patients were treated
for 6 weeks with salicylic acid applied once daily
and removed 12 h later. If progress was slow, a
shampoo containing 3% coal tar solution was
substituted for the shampoo. As a result, 90% of
in-patients and 65% of out-patients improved
with salicylic acid regarding scaling and
percentage of affected area and in one patient,
the scalp cleared completely. Scaling scores for
out-patients improved from baseline 7.0 to 4.5 at
6 weeks (n = 20; P\0.01) and the scores for in-
patients improved from baseline 7.7 to a score of
3.7 at 3 weeks (n = 10; P\0.001). Eight of the
out-patients, but none of the in-patients used the
coal tar shampoo. Out-patients used less salicylic
acid (27 g weekly) than in-patients (72 g weekly;
see Table 5) [55].
Combination Therapy
Concerning combination therapy with the super-
potent or potent corticosteroids betamethasone
dipropionateandmometasonefuroate,5randomized
controlled trials in a total of 1,248 patients were
identified. Patients with psoriasis were treated for
up to 3 weeks with a combination of 2% salicylic
acid and 0.05% betamethasone dipropionate
(2 studies; n = 72) or 5% salicylic acid and 0.1%
mometasonefuroate (3 studies; n = 519). The
respective control groups received the
corresponding corticosteroid only. In one
study, a more rapid onset of action and a more
rapid clearing of scaling, pruritus, and
inflammation was demonstrated with the
combination [56]; whereas in another trial, the
combination was statistically more effective than
the respective corticosteroid alone in terms of
mean total disease sign scores beginning at day 8
(P = 0.05) and continuing through days 15 and
22 (P\0.01) [46]. This is also reflected in theTa
ble
5co
ntin
ued
Ref
eren
ces
Inte
rven
tion
Tre
atm
ent
dura
tion
Pop
ulat
ion
Stud
yde
sign
Res
ults
Adv
erse
even
ts
Koo
etal
.[4
6]C
ombi
nati
onof
5%sa
licyl
icac
idan
d0.
1%m
omet
ason
efur
oate
oint
men
t
3w
eeks
408
pati
ents
wit
hm
oder
ate-
to-s
ever
eps
oria
sis
vulg
aris
Ran
dom
ized
,co
ntro
lled
stud
y
Sign
ifica
ntim
prov
emen
tof
the
inve
stig
ator
s’gl
obal
eval
uati
onof
over
all
clin
ical
resp
onse
atda
ys15
and
22(P
\0.
01)
and
indi
vidu
alsc
ores
for
scal
ing
(P=
0.01
)at
day
8,er
ythe
ma
and
indu
rati
onat
day
15(P
=0.
02an
d0.
03,
resp
ecti
vely
)co
mpa
red
tom
omet
ason
efur
oate
alon
e
App
licat
ion-
site
reac
tion
sin
9%of
pati
ents
vs.8
%w
ith
mom
etas
onef
uroa
teal
one
DL
QI
Der
mat
olog
yL
ifeQ
ualit
yIn
dex,
PASI
Psor
iasi
sA
rea
Seve
rity
Inde
x,PS
SIPs
oria
sis
Scal
pSe
veri
tyIn
dex
Dermatol Ther (Heidelb) (2015) 5:1–18 13
individual sign scores: the combination was
significantly more effective than the
corticosteroid alone for scaling starting on day
8 (P = 0.01), erythema (P\0.02), and pruritus on
day 14 (P\0.01) as well as induration on day 15
(P = 0.03), with P B 0.01 for all three signs of
psoriasis (erythema, induration and scaling) at
day 22 [46, 57]. According to the investigators’
global evaluation of overall clinical response,
patients treated with the combination showed a
better progress than those treated with the
corticosteroid alone (P\0.01) [46]. After 7 days
of treatment, a significantly greater reduction of
the Psoriasis Area Severity Index score was
observed compared to the corticosteroid alone
(P = 0.0017). Regarding the items of the
Dermatology Life Quality Index (DLQI)
questionnaire, data showed significant
differences in the ‘symptoms and feelings’
(P = 0.0464) and the ‘personal relationships’
items (P = 0.0378) [58]. On the self-assessment
questionnaire, patients preferred the
combination over the corticosteroid alone for
overall improvement of general appearance and
overall improvement of psoriasis (both P = 0.03;
see Table 5) [59]. In the evaluated studies, no
systemic toxicity was observed and absorption of
salicylate was negligible after application of 6%
to the scalp [55]. Yet application-site reactions
such as dryness, irritation, burning, pruritus, and
skin atrophy were reported (see Table 5) [46, 55,
58, 59].
DISCUSSION
This systematic literature review covering
articles published from January 1983 to
December 2013 identified several reviews,
meta-analyses, and guidelines emphasizing
that, while topical treatment with
corticosteroids and vitamin D analogs currently
represent first-line therapies, adjuvant therapy
with topical keratolytics and emollients forms
part of an integrated therapeutic concept. This is
in line with the evaluated studies demonstrating
specific properties of these agents that determine
their role within this concept.
Regarding emollients, the evaluated studies
provided some evidence that these agents play a
role as a basic therapy in supporting skin care
and improving the altered structure and
function of the skin but without a distinct
clinical response in psoriasis. Study results for
urea point to a reduction of induration and/or
scaling. However, the percentage of affected
area was not reduced. Due to its emollient and
keratolytic activity, urea may be used as a safe
basic therapy leading to increased patient
satisfaction. The same applies to AHAs and
PHAs. However, to date, there are only a
limited number of short-term studies regarding
the mentioned substances, which were mostly
performed in small populations without control
or a clear randomization procedure and mainly
using weak outcomes variables.
Salicylic acid represents the best studied
keratolytic compound to date. Although
salicylic acid used as monotherapy induced a
significant improvement of psoriasis, as
determined by the percentage of body surface
area involved and/or the overall degree of
erythema, induration, and desquamation [3,
55], the evidence of its efficacy as monotherapy
remains controversial due to the lack of larger,
high-quality trials and the absence of a placebo
control which is considered a major limitation
of most of the identified studies.
Only four of the studies included in this
review had a placebo control, that is, a
comparison with the cream vehicle. In three
of these studies, treatment with the active
14 Dermatol Ther (Heidelb) (2015) 5:1–18
substance (i.e., urea) led to a statistically
significant improvement of outcome
parameters compared to the vehicle [41]. In
two studies, the ointment base (which was not
further specified) also improved psoriasis, but
to a significantly lesser extent than the
pharmacologically active ingredient, urea [38,
42]. This is in line with the studies on
emollients, that may represent constituents
of an ointment base and that did not show
any relevant reduction in the severity of
psoriasis.
As regards its place in therapy, results of
the current literature analysis support the use
of salicylic acid as monotherapy in the
treatment of scalp psoriasis and as an
adjuvant agent in the treatment of other
skin areas affected by psoriasis. Yet, patient
adherence in scalp psoriasis is often poor due
to the longer contact times required and since
vehicles tend to be greasy [11]. In
combination with the super-potent or potent
corticosteroids betamethasone dipropionate
and mometasonefuroate, evidence from
several randomized controlled trials in a total
of 1,248 patients demonstrates that addition
of salicylic acid is beneficial in inducing a
more rapid onset of action and a reduction of
psoriasis determined by the percentage of
body surface area involved and/or the overall
degree of erythema, induration, and
desquamation. The addition of salicylic acid
led to a better investigators’ global evaluation
of overall clinical response, a more favorable
evaluation by patients and significant lower
DLQI scores compared to the respective
corticosteroid alone.
Since treatment outcome determines
treatment satisfaction, which in turn affects
medication adherence, keratolytic agents such
as salicylic acid may support overall adherence
to the prescribed therapy. While salicylic acid at
the applied concentrations was well tolerated in
the evaluated studies with no signs of systemic
toxicity, concerns of systemic toxicity are
consistently expressed in the literature [2, 3, 6,
7, 22, 27].
CONCLUSION
Considering that descaling and/or penetration
enhancement entails a distinct benefit in
patients with psoriasis improving patient
satisfaction and treatment adherence, there
still is a need for well-designed studies on the
currently available keratolytic agents but also
on suitable keratolytic alternatives to salicylic
acid with less potential for adverse effects. Cost-
effectiveness should also be addressed in future
studies.
ACKNOWLEDGMENTS
Sponsorship for this study and article
processing charges was funded by G. Pohl-
Boskamp GmbH & Co. KG, Hohenlockstedt,
Germany. All named authors meet the ICMJE
criteria for authorship for this manuscript, take
responsibility for the integrity of the work as a
whole and have given final approval for the
version to be published.
Conflict of interest. Arnd Jacobi, Anke
Mayer, and Matthias Augustin declare no
conflict of interest.
Compliance with ethics guidelines. This
review is based on previously conducted
studies, and does not involve any new studies
of human or animal subjects performed by any
of the authors.
Dermatol Ther (Heidelb) (2015) 5:1–18 15
Open Access. This article is distributed
under the terms of the Creative Commons
Attribution Noncommercial License which
permits any noncommercial use, distribution,
and reproduction in any medium, provided the
original author(s) and the source are credited.
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